Opioids agonists and antagonists

Opioid Analgesics
& Antagonists
Dr. Mahendra R Prajapati
MD Pharmacology
GSMC & KEM Hospital
Mumbai

Algesia (pain)
It is an ill-defined, unpleasant bodily sensation, usually
evoked by an external or internal noxious stimulus
Pain is a warning signal, primarily protective in nature, but
causes discomfort and suffering; may even be unbearable and
incapacitating
Tripathi KD. Essentials of medical pharmacology. JP Medical Ltd; 2013 Sep 30.

A drug that selectively relieves pain by acting in the CNS or on
peripheral pain mechanisms, without significantly altering
consciousness
Analgesic
Analgesics are divided into two groups
A. Opioid/narcotic/morphine-like analgesics
B. Nonopioid/non-narcotic-like antipyretic or
anti-inflammatory analgesics

1. Natural opium alkaloids: Morphine, Codeine
2. Semisynthetic opiates: Diacetylmorphine (Heroin),
Pholcodeine, Ethylmorphine
Many others like—Hydromorphone, Oxymorphone, Hydrocodone, Oxycodone
are not used in India
3. Synthetic opioids: Pethidine (Meperidine), Fentanyl,
Methadone, Dextropropoxyphene, Tramadol
Many others like—Levorphanol, Dextromoramide, Dipipanone, Alfentanil,
Sufentanil, Remifentanil are not available in India
CLASSIFICATION OF OPIOIDS

e.g. morphine is an agonist on μ, κ and δ receptors, but its affinity for μ receptors is much higher than
that for the other two. The effects, therefore, are primarily the result of μ receptor activation
Overall pattern of effect of a particular agent depends on the
 nature of its interaction with different opioid receptors
 its relative affinity for these
Opioid ligands can interact with different opioid receptors as
 Agonists
 partial agonists
 competitive antagonists
Each has a specific pharmacological profile + pattern of
anatomical distribution in the brain, spinal cord and peripheral
Tissues (mainly gut, blood vessels, heart, lungs and immune cells)
3 types (μ, κ, δ)
OPIOID RECEPTORS

 Cancer pain
 Mod to severe pain unresponsive to non-opioids
 Severe acute pain (Trauma, post-op)
 Chronic pain
 Neuropathic pain
Indications

Codeine
Relieve mild to moderate pain only
With a low ceiling effect
Partial agonist at μ opioid receptor
Less efficacious
Less potent than morphine (1/10th as analgesic)
Partly converted in the body to morphine

Codeine
The abuse liability is low
Codeine has been used to control diarrhoea
Constipation is a prominent side effect
Single oral dose acts for 4–6 hours
Codeine has good activity by the oral route
However, codeine is more selective cough suppressant

Pholcodeine, Ethylmorphine
Less constipating
Used mainly as antitussive
Have codeine like properties

Heroin (Diamorphine, Diacetylmorphine)
Banned in most countries except U.K
It has no outstanding therapeutic advantage over morphine
Because of its high potency, hence favoured in illicit drug trafficking
More euphorient (especially on i.v. injection) & highly addicting
More lipid soluble, therefore enters the brain
more rapidly, but duration of action is similar
3 times more potent than morphine

Methadone
Plasma protein binding is 90%
Slightly more potent than morphine
Firmly binding to tissue proteins
Analgesic, respiratory depressant, emetic, antitussive,
constipating and biliary actions similar to morphine
A synthetic opioid, pharmacologically very similar to morphine

Methadone
Methadone has been used primarily as substitution therapy for
opioid dependence: 1 mg of oral methadone can be substituted
for 4 mg of morphine, 2 mg of heroin and 20 mg of pethidine
It is probably incapable of giving a ‘kick’.
The abuse potential is rated lower than morphine.
Metabolized in liver & excreted in urine
Duration of action (4–6 hours on i.m. injection)

Dextropropoxyphene
Chemically related to methadone
But it is quite similar in analgesic action & in side effects
to codeine, except that it is a poor antitussive, probably
less constipating
Delirium and convulsions have occurred in overdose
Dextropropoxyphene (60–120 mg) is used as a mild oral analgesic
Metabolized in liver
T½ is variable (4–12 hours)

Dextropropoxyphene
Marketed only in combination with paracetamol ± other drugs
But the contribution of dextropropoxyphene to the
analgesic effect of the combination is questionable.
Because of reported fatalities and no clear advantage of the
combinations over paracetamol alone, such preparations have
been withdrawn in the UK and Europe, a warning has been put on
the labels in the US
Cardiac toxicity & seizures
are dangerous in overdose
Toxicity is only partly antagonized by naloxon

Tramadol
Tramadol causes less respiratory depression, sedation,
constipation, urinary retention and rise in intrabiliary
pressure than morphine.
t½ is 5–6 hours and effects last for 4–6 hrs
Oral bioavailability of tramadol is good
MOA: Its affects μ opioid receptor & it inhibits
reuptake of NA and 5-HT, increases 5-HT release,
and thus activates spinal inhibition of pain
Centrally acting analgesic

Tramadol
Dose: 50–100 mg oral/i.m./slow i.v. infusion (children 1–2
mg/ kg) 4–6 hourly
Abuse potential is low
Indicated for mild-to-moderate short-lasting pain due to
diagnostic procedures, injury, surgery, etc, as well as for chronic
pain including cancer pain, but is not effective in severe pain
Tramadol should not be given to patients taking SSRI therapy
because of risk of ‘serotonin syndrome’
Haemodynamic effects are minimal
Side effects are dizziness, nausea, sleepiness, dry mouth,
sweating and lowering of seizure threshold

OPIOID ANTAGONISTS
1. Agonist-antagonists (κ analgesics)
Nalorphine, Pentazocine, Butorphanol
2. Partial/weak μ agonist + κ antagonist
Buprenorphine
3. Pure antagonists
Naloxone, Naltrexone, Nalmefene

Nalorphine
Not used clinically because of dysphoric and
psychotomimetic effects
First opioid antagonist introduced in 1951
which could reverse morphine action
N-allyl-normorphine

Pentazocine
Though abuse liability is low, frequent side effects and
potential for dysphoric/ psychotomimetic effect limits
its utility in chronic (cancer) pain
Indicated for postoperative and moderately severe
pain in burns, trauma, fracture, cancer, etc
Duration of action of a single dose is 4–6 hours
Plasma t½ is 3–4 hours
Metabolized in liver and excreted in urine
Effective orally

Pentazocine
Other side effects are sweating and lightheadedness
Vomiting is less frequent
Biliary spasm and constipation
Tachycardia and rise in BP are produced at higher doses
due to sympathetic stimulation. This may increase
cardiac work; better avoided in coronary ischaemia
and myocardial infarction
Sedation and respiratory depression is
1/3 to 1/2 of morphine

Butorphanol
Dose of 1–4 mg i.m. or i.v. for postoperative and other
short-lasting (e.g. renal colic) painful conditions
Abuse potential of butorphanol is low
BP is not increased
Side effects are similar to pentazocine
Butorphanol 2 mg = pentazocine 30 mg
More potent than pentazocine

Buprenorphine
Sedation, vomiting, miosis, subjective and
cardiovascular effects are similar to morphine,
but constipation is less marked
Postural hypotension is prominent
After a single dose, analgesia lasts for 6–8 hours; but with
repeated dosing, duration of action increases to ~24 hours due
to accumulation in tissues
25 times more potent than morphine onset of action is slower
and duration longer
Highly lipid-soluble μ analgesic

Buprenorphine
Mostly excreted unchanged in bile and finds its way out of the
body in faeces
t½ is 40 hours
Highly plasma protein bound & remains in tissues for several
days
Buprenorphine has good efficacy by sublingual route
Naloxone (high dose) can prevent buprenorphine effect

Buprenorphine
Buprenorphine is not suitable for use during labour, because if
respiratory depression occurs in the neonate, it cannot be
effectively reversed by naloxone
It has also been recommended for premedication,
postoperative pain, in myocardial infarction and in the
treatment of morphine dependence
Use: Buprenorphine is indicated for long-lasting painful
conditions requiring an opioid analgesic, e.g. cancer pain
Dose: 0.3–0.6 mg i.m., s.c. or slow i.v., also sublingual 0.2–0.4
mg 6–8 hourly

Naloxone
However, sedation is less completely reversed
It promptly antagonizes all actions of morphine: analgesia
is gone, respiration is not only normalized but stimulated—
probably due to sudden sensitization of respiratory centre to
the retained CO2
Injected intravenously (0.4–0.8 mg)
Competitive antagonist on all types of opioid receptors
Naloxone also blocks the actions of endogenous opioid
peptides

Naloxone
Adverse effects of naloxone are uncommon;
may include rise in BP and pulmonary edema
Plasma t½ is 1 hour in adults and 3 hours in newborns
Injected i.v. it acts in 2–3 min
Naloxone is inactive orally because of high
first pass metabolism in liver
Naloxone is the drug of choice for morphine poisoning and for
reversing neonatal asphyxia due to opioid use during labour
It also partially reverses alcohol intoxication

Naltrexone
Naltrexone differs from naloxone
orally active & having a long duration of action (1–2 days)
which makes it suitable for ‘opioid blockade’ therapy of post-
addicts: 50 mg/day is given orally so that if the subject takes
his/her usual shot of the opioid, no subjective
effects are produced and the craving subsides
More potent than naloxone
Chemically related to naloxone
Nausea is a common side effect, another is headache
Alcohol craving is also reduced by naltrexone
High doses can cause hepatotoxicity

Nalmefene
Longer acting
Has higher oral bioavailability
Lacks hepatotoxicity
Same as naltrexone

They bind with high affinity to the opioid receptors
Their actions are blocked by naloxone
These peptides are active in very small amounts
A number of peptides having morphine-like actions were
isolated from mammalian brain, pituitary, spinal cord and g.i.t.
3 distinct families of opioid peptides
Endorphins
Enkephalins
Dynorphins

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